Crystal Structure of the Antioxidant Enzyme Glutathione Reductase Inactivated by Peroxynitrite
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As part of our studies on the nitric oxide-related pathology of cerebral malaria, we show that the antioxidative enzyme glutathione reductase (GR) is inactivated by peroxynitrite, with GR from the malarial parasite Plasmodium falciparum being more sensitive than human GR. The crystal structure of modified human GR at 1.9-A resolution provides the first picture of protein inactivation by peroxynitrite and reveals that this is due to the exclusive nitration of 2 Tyr residues (residues 106 and 114) at the glutathione disulfide-binding site. The selective nitration explains the impairment of binding the peptide substrate and thus the nearly 1000-fold decrease in catalytic efficiency (k(cat)/K(m)) of glutathione reductase observed at physiologic pH. By oxidizing the catalytic dithiol to a disulfide, peroxynitrite itself can act as a substrate of unmodified and bisnitrated P. falciparum glutathione reductase.
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The function of GR can be oxidatively inactivated at a Cys residue in the active site.
“Interestingly, the function of GR can be oxidatively inactivated at a Cys residue in the active site (372, 428).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [372]
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- Authors
- Savvides, S. N., Scheiwein, M., Böhme, C. C., Arteel, G. E., Karplus, P. A., Becker, K., & Schirmer, R. H.
- Affiliations
- Oregon State University (US)
- Heidelberg University (DE)
- Justus-Liebig-Universität Gießen (DE)
- Heinrich Heine University Düsseldorf (DE)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-01
- Volume
- 277
- Issue
- 4
- Pages
- 2779-2784
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2068301733
- Cited by
- 127
- References
- 59
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 3 · 2018: 7 · 2017: 4 · 2016: 2 · 2015: 8 · 2014: 10 · 2013: 4 · 2012: 11
- FWCI
- 2.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- glutathione reductase, peroxynitrite, protein nitration, tyrosine nitration, Plasmodium falciparum, cerebral malaria, nitric oxide, enzyme inactivation, crystal structure, catalytic efficiency, antioxidant enzymes
- MeSH terms
- Animals, Antioxidants, Binding Sites, Catalysis, Disulfides, Dose-Response Relationship, Drug, Flavins, Glutathione Reductase, Humans, Hydrogen-Ion Concentration, Kinetics, Models, Molecular, Nitrogen, Peptides, Plasmodium falciparum, Protein Binding, Spectrophotometry, Toluene, Tyrosine, Signal Transduction, Crystallography, X-Ray, Peroxynitrous Acid
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